Abstract
PurposeThe Göttingen minipig is a relevant non-rodent species for regulatory toxicological studies. Yet, its use with therapeutic antibodies has been limited by the unknown binding properties of human immunoglobulins (huIgG) to porcine Fc gamma receptors (poFcγR) influencing safety and efficacy readouts. Therefore, knowing IgG-FcγR interactions in the animal model is a prerequisite for the use of minipigs in preclinical safety and efficacy studies with therapeutic antibodies.MethodsHere, we describe the cloning and expression of poFcγRs and their interactions with free and complexed human therapeutic IgG1 by surface plasmon resonance and flow cytometry.ResultsWe show here that poFcγRIa, poFcγRIIa, and poFcγRIIb bind huIgG1 antibodies with comparable affinities as corresponding huFcγRs. Importantly, poFcγRs bind huIgG immune complexes with high avidity, thus probably allowing human-like effector functions. However, poFcγRIIIa binds poIgG1a but not to huIgG1.ConclusionsThe lack of binding of poFcγRIIIa to huIgG1 might cause underestimation of FcγRIIIa-mediated efficacy or toxicity as mediated by porcine natural killer cells. Therefore, the suitability of minipigs in preclinical studies with human therapeutic antibodies has to be assessed case by case. Our results facilitate the use of Göttingen minipigs for assessment of human therapeutic antibodies in preclinical studies.
Highlights
fragment crystallizable (Fc) gamma Receptors (FcγRs) are a family of gylcoproteins expressed on the surface of leukocytes
Due to the similar binding properties of FcγRIa, FcγRIIa, and FcγRIIb we suggest the minipig as a valuable species for assessment of immune complexes (IC)-mediated toxicities such as bevacizumab induced platelet activation
The limitations of the minipig relate to the failure of poFcγRIIIa to bind huIgG1 antibodies to mediate effects such as antibody-dependent cellular cytotoxicity (ADCC) as demonstrated by the influenza study in pigs with a huIgG1 antibody discussed before [41]
Summary
Fc gamma Receptors (FcγRs) are a family of gylcoproteins expressed on the surface of leukocytes They interact with the fragment crystallizable (Fc) part of immunoglobulin G (IgG) antibodies and trigger a variety of effector functions including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antigen internalization and presentation, or inflammatory cytokine release [1]. The set of FcγRs of most mammalian species consists of the high affinity FcγRIa (CD64), low affinity FcγRIIa (CD32a) and FcγRIIIa (CD16), and the inhibitory FcγRIIb (CD32b) [2]. Their cellular distribution and distinct affinities Page 2 of 13. It is very important to characterize the binding of free- and immune-complexed IgG to different FcγRs as this can dramatically influence safety and efficacy
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